Proteasome inhibitors attenuates mitoxantrone-triggered immunogenic cell death in prostate cancer cells

Area of Science:

• Oncology
• Immunology
• Cancer Cell Biology

Background:

• Mitoxantrone (MTX) and proteasome inhibitors are known to induce immunogenic cell death (ICD) in cancer cells.
• The potential synergistic effects of combining MTX with proteasome inhibitors on ICD have not been previously investigated.

Purpose of the Study:

• To investigate whether combining MTX with proteasome inhibitors (bortezomib/BZM and MG132) synergistically enhances ICD in prostate cancer cells.
• To determine the role of proteasome activation in MTX-induced ICD.

Main Methods:

• Assessed ICD biomarkers and dendritic cell activation in vitro following treatment with MTX alone or in combination with BZM or MG132 in prostate cancer cells.
• Evaluated tumor growth, tumor-free survival, and overall survival in mice vaccinated with RM-1 cells treated with MTX alone or in combination with BZM or MG132.

Main Results:

• Proteasome inhibitors BZM and MG132 impaired MTX-induced ICD in prostate cancer cells.
• Combination therapy with MTX and proteasome inhibitors resulted in enhanced tumor growth and reduced survival in a mouse model.
• MTX treatment alone was more effective than combination therapy.

Conclusions:

• Proteasome inhibitors (BZM or MG132) attenuate MTX-induced ICD.
• Proteasome activation is a required component for MTX to effectively induce ICD.